tert-Butyl 4-oxopiperidine-1-carboxylate → tert-Butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate

HRID 1507204Notes

Reaction equation

HRID 1507204 reaction equation
[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>C(OCC)C.O>[F:15][C:16]1[CH:17]=[C:18]([C:2]2([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]

Participants

5

Reactant 2

HCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 178491915HCID 178491915, compound

Product 1

HCID 118207351tert-Butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylateYield 88.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3283Diethyl EtherSolvent

Procedure

A stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (4.5 g, 22.6 mmol) in diethyl ether (100 mL) at 0° C. was treated with a solution of (3-fluoro-4-methoxyphenyl)magnesium bromide (49.7 mL, 24.8 mmol, 0.5 M in tetrahydrofuran). The reaction mixture was allowed to warm to rt and was stirred at for 12 h. It was then diluted with 100 mL water and the layers were separated. The aqueous layer was extracted three times with 150 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (120 g column) eluting with 30% ethyl acetate in petroleum ether to obtain 6.5 g of tert-butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate as a clear liquid; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.47 (m, 11H) 1.52-1.61 (m, 2H) 1.69-1.84 (m, 2H) 3.03-3.22 (m, 2H) 3.77-3.89 (m, 6H) 5.09 (s, 1H) 7.10 (s, 1H) 7.17-7.26 (m, 1H) 7.25-7.33 (m, 1H).

Workup

  1. customthe layers were separated
  2. extractionThe aqueous layer was extracted three times with 150 mL of ethyl acetate
  3. dry with materialthe combined organic layers were dried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. customevaporated
  6. customThe residue was purified by silica gel chromatography (120 g column)
  7. washeluting with 30% ethyl acetate in petroleum ether

Sources & evidence

ORD record
ord-a70adc5b88f742428596ed9a9219e923
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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